Hepatitis C virus (HCV) is a hepatotropic RNA virus that infects more than 200 million people worldwide. HCV is transmitted via percutaneous exposure to contaminated blood or blood products. Acute exposure to HCV most often leads to chronic infection characterized by persistent virus replication, hepatitis and the development of fibrosis and cirrhosis. The molecular basis for the hepatotropism of HCV has not been defined, in part, because of the lack of a suitable culture system by which to propagate native HCV infection. HCV binding and entry into the host cell is thought to occur through specific interactions of the HCV surface glycoproteins, E1 and E2, with surface proteins expressed on the target cell. We have adapted and developed new strategies by which to identify candidate HCV receptor proteins, and by which to assess the role of each candidate receptor in mediating the processes of virus binding and entry that direct HCV infection. We will utilize these novel strategies to investigate the hypothesis that HCV tropism is mediated by E1 and/or E2 glycoprotein interactions with liver-specific cell surface receptor proteins. In Aim 1 of this proposal we will utilize a cell-based expression/binding assay system to screen a liver-specific cDNA library for candidate cellular receptors that bind to one or both HCV glycoproteins. Aim 2 will employ a novel HCV-pseudotyped virus system to assess the role of each candidate receptor protein in supporting HCV binding and entry into the host cell. This pilot project will identify cellular HCV-binding proteins that direct viral tropism and that participate in the processes of HCV binding and entry. The proposed studies will provide novel insights into the HCV infectious cycle, and will establish a foundation for future work aimed at understanding the virus-cell interactions that confer HCV tropism and infection. [unreadable] [unreadable] [unreadable]